In the United States, prostate cancer is currently the most commonly diagnosed cancer and the second-leading cause of cancer death in men. Following earlier trends of fluctuating rates, prostate cancer rates have been since 2001 decreasing by 4.4% per year. Likewise, since the early 1990s, there has been a more substantial decrease in prostate cancer deaths among African American men than their white counterparts. Yet prostate cancer incidence and death rates among African Americans remain more than twice as high as those for whites. Furthermore, African American men and Jamaican men of African descent have the highest incidences of prostate cancer in the world. Many factors have been suggested to contribute to the higher prostate cancer incidence and mortality rates in African American men. For these men, over-expression of the androgen receptor (“AR”) and elevated luteinizing hormone (“LH”) levels have been associated with advanced disease progression. Although substantial efforts have been applied to identify agents with efficacy against prostate cancer, few treatment options, including classical chemotherapeutic agents, have not proven to be effective against this disease.
Lytic peptides are a ubiquitous feature of nearly all multi-cellular and some single-cellular life forms. They generally consist of between 10 and 40 amino acid sequences, which have potential for forming discrete secondary structures. Often, they exhibit the property of amphipathy (having both hydrophilic and lipophilic properties) because they may be depicted as a cylinder with one curved face composed primarily of nonpolar amino acids, while the other face is composed of polar amino acids. Most lytic peptides that have been previously described, appear to fall into one of three different classes based on the arrangement of amphipathy and high positive charge density within the molecule: Cecropins (35 amino acids in length and derived from the Giant Silk Moth), Magainins (23 amino acids in length and derived from the African Clawed Frog), and Melittin (26 amino acids in length and derived from the Honeybee). The conservation of these physical properties is a requisite for activity, but the requirements seem to be somewhat nonspecific in terms of amino acid sequence.
Recently, the design and use of lytic peptides for numerous cancers has been reported, including for prostate cancer. (See, for example, Hansel et al., “Conjugates of lytic peptides and LHRH or betaCG target and cause necrosis of prostate cancers and metastases,” Mol Cell Endocrinol 2007; 269:26-33, and Leuschner et al., “Human prostate cancer cells and xenografts are targeted and destroyed through luteinizing hormone releasing hormone receptors,” Prostate 2003; 56:239-49. Also, U.S. Pat. No. 6,635,740, issued to Enright et al., discloses amphipathic lytic peptides that comprise a ligand domain and a cytotoxin domain which may be used to target tumors, such as prostate cancer tumors, by using a hormone upon which the tumor is dependent as the ligand domain. The research of Hansel and Leuschner utilizing lytic peptides conjugated with luteinizing hormone-releasing hormone (“LHRH”) has indicated the importance of a steroid presence (see also, Leuschner et al., “Targeting breast and prostate cancers through their hormone receptors.” Biol. Reprod. 2005; 73:860-5; Hansel et al., “Targeted destruction of prostate cancer cells and xenografts by lytic peptide-betaLH conjugates.” Reprod. Biol. 2001; 1:20-32; Hansel et al., “Destruction of breast cancers and their metastases by lytic peptide conjugates in vitro and in vivo.” Mol. Cell. Endocrinol. 2007; 260-262:183-9; and Leuschner et al., “Membrane disrupting lytic peptide conjugates destroy hormone dependent and independent breast cancer cells in vitro and in vivo.” Breast Cancer Res. Treat. 2003; 78: 17-27). Namely, the work of those researchers indicate that presence of a circulating estradiol or follicle-stimulating hormone is necessary for their lytic compounds to be active; the removal of the steroids that they used from the culture media eliminated the sensitivity of prostate cancer cells to the effects of their lytic peptide-LHRH conjugates. It would be desirable if lytic peptides were identified that were highly active and non-toxic absent a hormone presence.
Early stage prostate cancers are androgen dependent, and thus can be treated in part via hormone therapy. Most hormone dependent cancers become refractory (i.e., hormone independent) after one to three years and resume growth despite hormone therapy. Hormone-refractory prostate cancer is a late stage of prostate cancer for which better treatments are needed. Thus, therapies directed at preventing or limiting the tumor's transition to the more aggressive invasive and metastatic stages offer benefits different from the present therapies that were designed to kill prostate cancer cells.
Thus, there remains a need in the art for improved treatments for prostate cancer that are highly effective in causing disease remission and in preventing progression of the disease to more advanced and aggressive stages while still exhibiting low toxicity.